The power of the Mediator complex-Expanding the genetic architecture and phenotypic spectrum of MED12-related disorders.

MED12 is a member of the large Mediator complex that controls cell growth, development, and differentiation. Mutations in MED12 disrupt neuronal gene expression and lead to at least three distinct X-linked intellectual disability syndromes (FG, Lujan-Fryns, and Ohdo). Here, we describe six families with missense variants in MED12 (p.(Arg815Gln), p.(Val954Gly), p.(Glu1091Lys), p.(Arg1295Cys), p.(Pro1371Ser), and p.(Arg1148His), the latter being first reported in affected females) associated with a continuum of symptoms rather than distinct syndromes. The variants expanded the genetic architecture and phenotypic spectrum of MED12-related disorders. New clinical symptoms included brachycephaly, anteverted nares, bulbous nasal tip, prognathism, deep set eyes, and single palmar crease. We showed that MED12 variants, initially implicated in X-linked recessive disorders in males, may predict a potential risk for phenotypic expression in females, with no correlation of the X chromosome inactivation pattern in blood cells. Molecular modeling (Yasara Structure) performed to model the functional effects of the variants strongly supported the pathogenic character of the variants examined. We showed that molecular modeling is a useful method for in silico testing of the potential functional effects of MED12 variants and thus can be a valuable addition to the interpretation of the clinical and genetic findings.

Running shoes and running injuries: mythbusting and a proposal for two new paradigms: 'preferred movement path' and 'comfort filter'.

In the past 100 years, running shoes experienced dramatic changes. The question then arises whether or not running shoes (or sport shoes in general) influence the frequency of running injuries at all. This paper addresses five aspects related to running injuries and shoe selection, including (1) the changes in running injuries over the past 40 years, (2) the relationship between sport shoes, sport inserts and running injuries, (3) previously researched mechanisms of injury related to footwear and two new paradigms for injury prevention including (4) the 'preferred movement path' and (5) the 'comfort filter'. Specifically, the data regarding the relationship between impact characteristics and ankle pronation to the risk of developing a running-related injury is reviewed. Based on the lack of conclusive evidence for these two variables, which were once thought to be the prime predictors of running injuries, two new paradigms are suggested to elucidate the association between footwear and injury. These two paradigms, 'the preferred movement path' and 'the comfort filter', suggest that a runner intuitively selects a comfortable product using their own comfort filter that allows them to remain in the preferred movement path. This may automatically reduce the injury risk and may explain why there does not seem to be a secular trend in running injury rates.

Mosaic trisomy 21/monosomy 21 in a living female infant.

Many autosomal monosomies are presumed to end in arrested growth in the first few mitoses, prior even to the time of implantation, with possibly some proceeding to the stage of occult abortion. The single exception may be monosomy 21, although this has been questioned, with most earlier reports of monosomy 21 recently re-interpreted as being due to an unbalanced translocation involving chromosome 21. Here we report a female infant with a mosaic trisomy 21/monosomy 21 karyotype. While the karyotype 46,XX,i(21)(q10) is detected in all metaphases investigated in lymphocytes, mosaicism with the karyotype 46,XX,i(21)(q10)[31]/45,XX, -21[12] is seen in fibroblasts from a skin biopsy. Dysmorphic facial features and multiple malformations remarkably resemble cases of monosomy 21 that have been described in the literature. This suggests a dominant phenotypic effect of loss of one chromosome 21. Detailed clinical description, results of gene dosage studies, and cytogenetic analysis will be presented.

De novostructural chromosomal imbalances: molecular cytogenetic characterization of partial trisomies.

De novo structural chromosomal imbalances represent a major challenge in modern cytogenetic diagnostics. Based solely on conventional cytogenetic techniques it may be impossible to identify the chromosomal origin of additional chromosomal material. In these cases molecular cytogenetic investigations including multicolor-FISH (M-FISH), spectral karyotyping (SKY), multicolor banding (MCB) and cenM-FISH combined with appropriate single-locus FISH probes are highly suitable for the determination of the chromosomal origin and fine characterization of derivative chromosomes. Here we report on four patients with de novo chromosomal imbalances and distinct chromosomal phenotypes, three of them harboring pure partial trisomies: a mildly affected boy with pure partial trisomy 10q22.2-->q22.3 approximately 23.1 due to an interstitial duplication, a girl with pure trisomy 12p11.21-->pter and atypically moderate phenotype as the consequence of an X;autosome translocation, and a girl with multiple congenital abnormalities and severe developmental delay and a 46,XX,15p+ karyotype hiding a trisomy 17pter-->17q11.1. The fourth patient is a girl with minor phenotypic features and mental retardation with an inverted duplication 18q10-->p11.31 combined with a terminal deletion of 18p32. The clinical pictures are compared with previously described patients with focus on long term outcome.

Partial tetrasomy 12pter-12p12.3 in a girl with Pallister-Killian syndrome: extraordinary finding of an analphoid, inverted duplicated marker.

Cytogenetic analysis in a girl with multiple congenital anomalies indicating Pallister-Killian syndrome (PKS) showed a supernumerary marker chromosome in 1/76 lymphocytes and 34/75 fibroblast metaphases. GTG-banding pattern was consistent with the chromosomal region 12pter-12q11. While fluorescence-in-situ hybridisation (FISH) with a whole chromosome 12 painting probe confirmed the origin of the marker, a chromosome 12 specific alpha-satellite probe did not hybridise to it. FISH analysis with a specific subtelomeric probe 12p showed hybridisation to both ends of the marker chromosome. High-resolution multicolour-banding (MCB) studies revealed the marker to be a der(12)(pter-->p12.3::p12.3-->pter). Summarising the FISH information, we defined the marker as an inverted duplication of 12pter-12p12.3 leading to partial tetrasomy of chromosome 12p. In skin fibroblasts, cultured at the patient's age of 1 year and 9 years, the marker chromosome was found in similar frequencies, even after several culture passages. Therefore, we consider the marker to have a functional centromere although it lacks detectable centromeric alpha-satellite sequences. To the best of our knowledge, this is the first proven analphoid marker of chromosome 12. Molecular genetic studies indicated that this marker is of paternal origin. The finding of partial tetrasomy 12pter-12p12.3 in our PKS patient allows to narrow down the critical region for PKS.

Restrictive dermopathy: report and review.

Restrictive dermopathy (RD) is a lethal autosomal recessive genodermatosis (MIM No. 275210) in which tautness of the skin causes fetal akinesia or hypokinesia deformation sequence (FADS). Polyhydramnios with reduced fetal movements is followed by premature delivery at around 31 weeks gestation. Manifestations include a tightly adherent, thin, translucent skin with prominent vessels, typical facial changes, generalized joint contractures, enlarged fontanelles, dysplasia of clavicles, respiratory insufficiency, and an enlarged placenta with short umbilical cord. Histologic abnormalities of the skin include thin dermis with paucity and hypoplasia of the appendages and abnormally arranged collagen bundles. Elastic fibers are nearly missing. The subcutaneous fat is slightly increased. These skin findings usually appear after 22 or 24 weeks of gestation, which is why prenatal diagnosis with skin biopsy may fail. This disease is easily differentiated from other congenital FADS, such as Pena-Shokeir syndrome, COFS syndrome, Parana hard-skin syndrome, etc. We report on an affected boy of consanguineous parents and 30 previous cases are reviewed.

New case of mosaic tetrasomy 9p with additional neurometabolic findings.

Tetrasomy 9p is a rare chromosomal aberration that was described in 28 previous patients. Here we report on a newborn girl who was referred for genetic evaluation because of developmental delay, hypertonicity, microcephaly, minor anomalies, and neurometabolic findings. She had an isochromosome 9p (pter --> p10 --> pter) in 32% of blood cells. The extra chromosome was not found in amniocytes. Examination of fibroblasts from different skin biopsies also showed mosaicism in this tissue. In a first biopsy from the abdominal wall, the cells (n = 50) had a normal chromosomal complement. Further analysis of fibroblasts from the left forearm showed the isochromosome 9p in 5 out of 8 mitoses. Fluorescence in situ hybridization (FISH), using a whole chromosome 9 probe, confirmed that the extra marker was 9 in origin. Molecular studies showed that the isochromosome was of maternal origin. Meiotic nondisjunction was followed by centromeric misdivision and postzygotic loss of the marker.

Bilaterally cleft lip, limb defects, and haematological manifestations: Roberts syndrome versus TAR syndrome.

We report on a 13-year-old patient followed since birth. He is the only offspring of young, non-consanguineous German parents. His mother has an isolated left cleft of lip and a cleft palate. At birth, our patient presented with bilaterally cleft lip/cleft palate, phocomelia of upper limbs with normal hands, and mild symmetrical deficiencies of the long bones of the lower limbs. Haematological evaluation demonstrated a leukaemoid reaction during a urinary tract infection as well as intermittent thrombocytopenia and episodes of marked eosinophilia during the first two years of life. Intellectual development has been normal. Comparison with two similar cases from the literature suggests a non-random phenotypic overlap of Roberts syndrome (MIM 268300) and TAR syndrome (MIM 274000). Such clinical constellations may be key observations to understand the genetic relationship of Roberts syndrome and TAR syndrome in future phenotype-genotype correlations.

Growth hormone (GH), insulin-like growth factors (IGFs), and IGF-binding protein-3 (IGFBP-3) in a child with Proteus syndrome.

Proteus syndrome is a congenital hamartomatous disorder characterized by partial overgrowth involving all germ layers. A somatic mutation model has been proposed since familial cases are extremely rare. We report on a 3-year-old girl with typical manifestations of Proteus syndrome, including local, asymmetric hypertrophy of various parts of the body. Total body length was reduced. Serum levels of IGF-I and especially IGF-II and their major growth hormone dependent binding protein (IGFBP-3) were significantly reduced, although growth hormone secretion after a pharmacological stimulus was normal. In vitro studies of fibroblasts derived from hypertrophied tissue showed normal IGF-I production and somewhat reduced IGF-II and IGFBP-3 production as compared to normal human skin fibroblasts. Affinity cross-linking experiments showed that fibroblasts of the affect tissue in Proteus syndrome produced an unusual pattern of IGF bindings proteins containing large amounts of an IGFBP with high affinity to IGF-II. The data suggest that IGF production is generally disturbed in Proteus syndrome with imbalanced levels of specific IGFBP in affected tissue.

Involvement of 22q13.3 in chromosomal-anomalies.

In a series of neoplasms involvement of chromosome 22, mainly concerning loci within bands 22q11-q12 has been reported. Yet, little is known about chromosomal anomalies in 22q13. As loss of heterozygosity in two neurofibromatosis type 2 patients was described in a 22q13.3 locus and deletions in the 22q13.3 chromosomal region were noted in a set of 7 patients, we decided to apply several newly isolated cosmids from 22q13 to analyse additional cases with chromosome 22 anomalies. In addition, the study was aided by centromeric probes and chromosome 22 painting. Fluorescent in situ hybridization with new cosmids mapping to 22q13.1 and 22q13.3 did not indicate deletions or rearrangements in one neurofibromatosis type 2 case [r(22)], a bisatellited chromosome 22 and in a translocation case [t(Y;22)].

Chromosomal and genetic forms of growth failure.

This chapter does not deal with single diseases, but gives a general account of chromosomal and genetically caused disturbances of growth; even a complete list and description of the various disorders would, in view of the large number of syndromes involving short stature, exceed its scope. Many chromosomal aberrations are non-viable disturbances of growth that lead to intrauterine amniotic death. Following a brief account of the normal development of the germ cell (gametogenesis, embryogenesis, phenogenesis) to the newborn, the incidence of the various chromosomal disturbances in the different stages of development and the effects on growth are discussed. In the case of chromosomal aberrations, particular attention is paid to the significance of mosaic formation. In addition, the new phenomena of genomic imprinting and uniparental disomy, exemplified by the Prader-Willi syndrome, are dealt with. Uniparental disomy, which was first demonstrated with the aid of molecular genetics, may provide an explanation for the sporadic appearance of many syndromes involving short stature. Many genes and environmental influences are involved in the individual shaping of body size so that a systematic classification of the various syndromes involving short stature is not possible. Finally, attention is drawn to the increased rate of formation of malignant tumours in certain syndromes involving disturbances of growth.

[Cardio-facio-cutaneous syndrome--visual diagnosis of a rare syndrome]. / Das Cardio-Facio-Cutane Syndrom--Blickdiagnose eines seltenen Syndroms.

This is a report of a case of cardio-facio-cutaneous (CFC) syndrome in a three-year-old boy. Apart from obvious signs of retardation in his mental and motor development, the child was conspicuous through his short stature, relative macrocephaly, vitium cordis, pendular nystagmus and ptosis and optic atrophy on both sides. The typically dysmorphic facial features that characterize this syndrome such as high forehead, biparietal impression, downward slant of the palpebral fissures, hypoplastic supraorbital ridges, depressed nasal bridge, high palate, and dysplasia of the ears, were particularly marked in this case. The hands and feet were plump, the skin rather thick, and the hair sparse and very curly. A chromosome analysis as well as metabolism tests proved normal. Until now there have been 27 reports of such cases in medical literature.

Consanguinity in a Turkish family with thrombocytopenia with absent radii (TAR) syndrome.

Two sibs with TAR syndrome and whose parents are blood relatives are described. To our knowledge this is the first report of consanguinity in TAR syndrome.

Retrospective diagnosis of trisomy 15 in formalin-fixed, paraffin-embedded placental tissue in a newborn girl with Prader-Willi syndrome.

Paternal deletion of 15q11-q13 and maternal uniparental disomy (UPD) of chromosome 15 are the main causes of Prader-Willi syndrome (PWS). The finding of an UPD(15) is associated with increased maternal age. We present a retrospective diagnosis of a trisomy 15 mosaicism confined to the placenta (CPM) after birth of a girl with clinical features of PWS born to a 43-year-old mother. Chromosome analysis after amniocentesis, performed because of advanced maternal age, had shown a normal female karyotype. In peripheral blood cells molecular studies showed the absence of the paternal allele at the SNRPN locus and fluorescence in situ hybridization (FISH) analysis excluded a deletion of the SNRPN locus on both chromosomes 15. Trisomic cells were detected by FISH on nuclei isolated from formalin-fixed, paraffin-embedded placental tissue using a DNA-probe specific for the centromeric region of chromosome 15.

Serpentine fibula--polycystic kidney syndrome and Melnick-Needles syndrome are different disorders.

We report on the third patient with serpentine fibula-polycystic kidney syndrome. Main features in the three reported cases were growth retardation, abnormal face, hirsutism, short neck, bowed forearms and lower legs due to bowed radii and elongated serpentine fibulae, and metatarsus adductus. Two patients including our own were deaf. All were mentally normal, all were female and sporadic. In addition, we report on a girl with Melnick-Needles syndrome and illustrate the similarities and differences between these syndromes.

A 47,XXY female with unusual genitalia.

A 47,XXY karyotype was found in a 6-year-old girl. The patient had female external genitalia, clitoromegaly, remnants of the ductus mesonephricus, uterus, and gonads in the labia majora which were determined to be testes by histology. Cytogenetic and DNA analyses suggest that the Y chromosome had a normal structure and that both X chromosomes were of maternal origin. The unusual clinical findings in the patient are discussed.

A family with combined Farber and Sandhoff, isolated Sandhoff and isolated fetal Farber disease: postnatal exclusion and prenatal diagnosis of Farber disease using lipid loading tests on intact cultured cells.

UNLABELLED: An earlier described patient with combined sphingolipidoses, Farber and Sandhoff disease, had two healthy older brothers and two further sibs, one with Sandhoff disease and one (a fetus) with Farber disease, showing segregation of the respective genes. The prenatal diagnosis in the latter was performed using lipid (sphingomyelin and glucosylceramide) loading tests on the cultured amniotic fluid cells. After 1-3 days of incubation the cells' lipid extract revealed radioactive ceramide to be released and highly accumulated. The deficiency in acid ceramidase was known from the patient with the combined diseases. Confirmation of the prenatal Farber diagnosis was done by similar loading tests on the fetal fibroblasts and by analysis of liver lipids of the less than 18-week-old fetus. CONCLUSION: This is the first report on the use of lipid loading tests on intact cultured cells for prenatal diagnosis of Farber disease. The postnatal diagnosis of Farber disease can also be readily made using those tests, as was shown in four further cases.

[Syndactylism of the hand. Pathogenetic and therapeutic aspects (author's transl)]. / Atiopathogenetische und therapeutische Gesichtspunkte zur Syndaktylie der Hand.

The latest concepts of the genetics of isolated syndactyly are described in relation to a case in which the malformation could be traced back to four generations. The different principles of classification of syndactyly and the therapeutic possibilities are discussed, calling special attention to early operation in infants.